Increasing evidence indicates that the earliest events in acute HIV infection likely define the subsequent course of disease. Thus, the need for comprehensive studies of the acute stage of infection in humans is critical for a better understanding of the correlates of immune protection and is likely to also be extremely important for the development of effective vaccines and immunotherapies. Meaningful insights are most likely to require study of large groups of persons with acute infection. To this end, we have established collaboration between two groups (Boston and Sydney), each with extensive experience in identifying persons with acute HIV infection and with documented ability to enroll such subjects in pathogenesis and intervention trials. Contributions from these investigators include 1) the first demonstrations that acute infection is associated with a clinical syndrome suggesting the diagnosis; 2) the linking of severity of acute infection symptoms to long-term progression of infection; 3) the demonstration that early treatment of acute infection enhances critical CD4 cellular immune responses; 4) the demonstration that such early intervention can at least transiently enhance immune control following treatment interruption; and 5) that immune selection pressure influences viral evolution and transmission. However, major questions remain to be addressed and are best addressed in the context of larger cohort studies. To effectively address these questions, we propose to join forces and investigate in detail issues related to the diagnosis, pathogenesis and treatment of acute HIV infection. Specifically, we propose to 1 ) establish networks to identify, recruit and follow-up persons with acute and early HIV infection; 2) conduct HIV pathogenesis studies using subjects who have not undergone treatment to determine the fundamental immunological correlates of viral control in HIV infection; 3) initiate randomized treatment studies to examine the effect both clinically and virologically of manipulating the immune responses in persons with acute infection; and 4) conduct corresponding pathogenesis studies on treated subjects with acute infection and determine the impact of therapy on immunologic and virologic factors.